Radiopharmaceutical compositions of radioactive halogenated benzylguanidine

ABSTRACT

The present disclosure concerns radiopharmaceutical compositions of radioactive halogenated benzylguanidine (such as radioiodinated MIBG) or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In a preferred embodiment, the composition has at least 97% of radiochemical purity for at least 4 days. Advantageously, the compositions of the present disclosure may be devoid of parabens, which are carcinogenic and yet are used in known radioactive MIBG compositions. The present disclosure also provides processes of preparing a radioactive halogenated benzylguanidine composition. The compositions of the present disclosure can be used in diagnosis and treatment of various diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/447,155, filed Jun. 20, 2019, which claims priority to U.S.Provisional Application No. 62/688,470, filed on Jun. 22, 2018, theentire contents of which are herein incorporated by reference.

FIELD

The present disclosure is concerned with radiopharmaceuticalcompositions of radioactive halogenated benzylguanidine (such asradioactive iodine MIBG), or a pharmaceutically acceptable salt, hydrateor solvate thereof. In a preferred embodiment, the compositions have atleast 97% of radiochemical purity for at least 4 days. Advantageously,the compositions of the present disclosure may be devoid of parabens,which are found to be carcinogenic and yet are used in knowncompositions for stabilizing MIBG compositions. The present disclosurealso provides processes of preparing a radioactive halogenatedbenzylguanidine composition. The compositions of the present disclosurecan be used in diagnosis and treatment of various diseases.

BACKGROUND

Radioactive iodine MIBG is a radiopharmaceutical used in a scintigraphymethod called MIBG scan. The radioisotope of iodine that is commonlyused for labeling is ¹²³I or ¹³¹I. ¹³¹I-MIBG also called IobenguaneSulfate I-131 Injection, is used as an adjunctive diagnostic agent inthe localization of primary or metastatic pheochromocytomas andneuroblastomas. MIBG has a structural formula as represented in FormulaI.

Radioactive iodine MIBG is used in radiopharmaceutical compositions. Itwas marketed by Pharmalucence Inc. as a solution for intravenousinjection (formulation discontinued as per USFDA). This radioactiveiodine MIBG composition contains iobenguane sulfate, 85.1 MBq (2.30 mCi)of ¹³¹I (as iobenguane sulfate ¹³¹I at calibration), sodium acetate,acetic acid, sodium chloride, methyl paraben, propyl paraben and benzylalcohol. This composition contains parabens such as methyl and propylparaben and it is known that use of parabens is not safe and can lead tocertain tumors like breast tumors (Rita Arditti (Jun. 9, 2004).“Cosmetics, parabens, and breast cancer”. Organic ConsumersAssociation).

U.S. Pat. No. 4,880,615 discloses use of radioprotectants likenicotinamide, nicotinic acid and ascorbic acid in order to stabilizeradioactive MIBG compositions. However, examples shown in this patentwere unable to achieve radiochemical purity of more than 96% for fourdays. Since stability, high radiochemical purity during the shelf lifeis critical for commercialization of any radiopharmaceutical product,there exists a need to improve the stability and radiochemical purity of¹²³I or ¹³¹I MIBG compositions using iodinated MIBG having highactivity.

Other radioisotopes are used for labelling cold MIBG, such as ²¹¹At, ¹⁸Fand ⁷⁶Br. Labelling cold MIBG with astatine-211 providesmeta-²¹¹At-astato-benzylguanidine (²¹¹At-MABG), and this radio-analogdiscussed by Ohshima et al. Eur. J. Nucl. Med. Mol. Imaging. 2018, 45(6)pp. 999-1010. Labelling cold MIBG with fluor-18 leads to ¹⁸F-MetaFluorobenzyl Guanidine (¹⁸F-MFBG), which was reported by Pandit-Taska etal. J. of Nucl. Med., Published online Jul. 13, 2017 (Doi:10.2967/jnumed.117.193169). Labelling cold MIBG with bromo-76 results inm-bromo-benzylguanidine (⁷⁶Br-MBBG) and its use as an alternative to¹³¹I-MIBG was discussed in Jérôme Clerc thesis in 1997(http://www.theses.fr/1997PA112206).

SUMMARY

-   -   The present disclosure provides radiopharmaceutical compositions        of radioactive halogenated benzylguanidine that has a high        radioactive purity.    -   The present inventors have surprisingly found that stable        compositions of radioactive MIBG or its pharmaceutically        acceptable salts, hydrates and solvates thereof can be made        without use of parabens in the composition. It has been        surprisingly found that maintaining a ratio of radioprotectants        like benzyl alcohol and niacinamide in the composition leads to        a stable composition with radiochemical purity of at least 97%        for at least four days. The combination of benzyl alcohol and        niacinamide provides synergistic effect in stabilizing        radiopharmaceutical compositions of the present disclosure.    -   The present disclosure also provides radiopharmaceutical        compositions of radioactive halogenated benzylguanidine having a        high radioactive purity that remain stable for a suitable period        of time which covers the period from their preparation,        transportation and administration to the patient. Preferably,        this suitable period is of 2, 3, 4, or 5 days.    -   The present disclosure further provides radiopharmaceutical        compositions of radioactive halogenated benzylguanidine that are        exempt of paraben.    -   The present disclosure concerns any of the following Aspects:    -   Aspect 1. A radiopharmaceutical composition comprising a        radiohalogenated benzylguanidine or a pharmaceutically        acceptable salt, hydrate or solvate thereof, wherein the        composition has a radiochemical purity of at least 95% at two        days following its preparation from its constituent ingredients.    -   Aspect 2. The radiopharmaceutical composition of aspect 1,        wherein the radiochemical purity is at least 95% at four days        following its preparation.    -   Aspect 3. The radiopharmaceutical composition of aspect 1 or        aspect 2, wherein the radiochemical purity is at least 97% at        two days following its preparation.    -   Aspect 4. The radiopharmaceutical composition of any preceding        aspect, wherein the radiochemical purity is at least 97% at four        days following its preparation.    -   Aspect 5. The radiopharmaceutical composition of any preceding        aspect, wherein the composition has a radiochemical purity of at        least 99% at the time immediately following its preparation.    -   Aspect 6. The radiopharmaceutical composition of any preceding        aspect, the radiohalogenated benzylguanidine or a        pharmaceutically acceptable salt, hydrate or solvate thereof,        contains a radioactive halogen which is selected from the group        consisting of ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ²¹¹At, ¹⁸F and ⁷⁶Br.    -   Aspect 7. The radiopharmaceutical composition of aspect 6,        wherein radioactive halogen which is selected from the group        consisting of ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I.    -   Aspect 8. The radiopharmaceutical composition of aspect 7,        wherein radioactive halogen is ¹³¹I.    -   Aspect 9. The radiopharmaceutical composition of any preceding        aspect, wherein the composition does not include a paraben.    -   Aspect 10. The radiopharmaceutical composition of any preceding        aspect, wherein the composition has a radiochemical purity of at        least 95% at two days following its preparation when stored at        any temperature from 78±3° C. to 25±3° C.    -   Aspect 11. The radiopharmaceutical composition of any preceding        aspect, wherein the composition has a radiochemical purity of at        least 95% at two days following its preparation when stored at a        temperature of 5±3° C.    -   Aspect 12. The radiopharmaceutical composition of any preceding        aspect, comprising benzyl alcohol and niacinamide.    -   Aspect 13. The radiopharmaceutical composition of aspect 12,        wherein the benzyl alcohol and niacinamide are present in the        composition in a ratio of from 1:0.5 to 1:35.    -   Aspect 14. The radiopharmaceutical composition of aspect 13,        wherein the benzyl alcohol and niacinamide are present in the        composition in a ratio of from 1:0.8 to 1:32.    -   Aspect 15. The radiopharmaceutical composition of aspect 14,        wherein the benzyl alcohol and niacinamide are present in the        composition in a ratio of about 1:1.    -   Aspect 16. The radiopharmaceutical composition of aspect 14,        wherein the benzyl alcohol and niacinamide are present in the        composition in a ratio of about 1:0.8.    -   Aspect 17. The radiopharmaceutical composition of aspect 12,        wherein the benzyl alcohol is present in a concentration from        0.9% (v/v) to 2.0% (v/v).    -   Aspect 18. The radiopharmaceutical composition of aspect 12,        wherein the composition has a pH from 3.0 to 7.0.    -   Aspect 19. The radiopharmaceutical composition of aspect 18,        wherein the pH is 5.0±0.1.    -   Aspect 20. The radiopharmaceutical composition of aspect 18,        further comprising a buffer comprising sodium acetate and sodium        chloride.    -   Aspect 21. The radiopharmaceutical composition of aspect 12,        wherein the composition is prepared by a method comprising the        steps of:    -   (i) combining benzyl alcohol with water to form a combination;    -   (ii) adding niacinamide to the combination of step (i), and        mixing;    -   (iii) adjusting the pH of the combination from 3.0 to 7.0; and    -   (iv) adding radiohalogenated benzylguanidine to the pH-adjusted        combination of step (iii);    -   and wherein the method does not include the addition of paraben.    -   Aspect 22. The radiopharmaceutical composition of aspect 21,        wherein step (ii) of the method further comprises the addition        of sodium acetate and sodium chloride.    -   Aspect 23. The radiopharmaceutical composition of any preceding        aspect, wherein the composition is a lyophilized powder,        solution, suspension or emulsion.    -   Aspect 24. The radiopharmaceutical composition of any preceding        aspect, wherein the composition is provided in a container        selected from the group consisting of a vial, an ampoule, a        prefilled syringe, and a capsule.    -   Aspect 25. A method for the detection or localization in a        subject of primary or metastatic pheochromocytoma,        neuroblastoma, paraganglioma, neuroendocrine tumor of        gastroenteropancreatic tract, medullary thyroid carcinoma, or a        disease resulting from myocardial ischemia and cardiomyopathy,        the method comprising    -   administering to the subject the radiopharmaceutical composition        according to any of aspects 1-24, and,    -   performing scintigraphic imaging in order to detect or localize        the primary or metastatic pheochromocytoma, neuroblastoma,        paraganglioma, neuroendocrine tumor of gastroenteropancreatic        tract, medullary thyroid carcinoma, or a disease resulting from        myocardial ischemia and cardiomyopathy in the subject.    -   Aspect 26. A method for diagnosing or treating in a subject        pheochromocytoma, neuroblastoma, paraganglioma, or        neuroendocrine tumor of the gastroenteropancreatic tract, the        method comprising administering to the subject the        radiopharmaceutical composition according to any of aspects        1-24.

The scope of the presently disclosed subject matter will be betterunderstood in light of the following detailed description thereof.

DETAILED DESCRIPTION

In one aspect, provided herein are radiopharmaceutical compositions ofradiohalogenated benzylguanidine, a pharmaceutically acceptable saltthereof, a pharmaceutically acceptable hydrate thereof, or apharmaceutically acceptable solvate thereof. It should be understoodherein that the expression “a pharmaceutically acceptable salt thereof,a pharmaceutically acceptable hydrate thereof, or a pharmaceuticallyacceptable solvate thereof” has the exact same meaning herein than “apharmaceutically acceptable salt, hydrate or solvate thereof” and thelatter is used for sake of conciseness. Radioactive halogenatedbenzylguanidine includes radioactive iodine metaiodobenguanidine(radioactive iodine MIBG or radioiodinated MIBG) that contains an iodineradioisotope, which is preferably selected from the group consisting of¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Benzylguanidine and benguanidine are usedinterchangeably herein. Also, the terms “radiohalogenated” and“radioactive halogenated” are used interchangeably herein and areintended to mean the same. The expression “m-iodobenzylguanidine” can beused interchangeably with “metaiodobenzylguanidine”,“metaiodobenguanidine”, “MIBG”, and “iobenguane”.

In another aspect, the radiopharmaceutical compositions of the presentdisclosure comprise radioactive halogenated benzylguanidine or apharmaceutically acceptable salt, hydrate or solvate thereof, whereinthe radioactive halogenated benzylguanidine contains a radioactivehalogen which is preferably selected from the group consisting of ¹²³I,¹²⁴I, ¹²⁵I, ¹³¹I, ²¹¹At, ¹⁸F and ⁷⁶Br. The radioactive halogenatedbenzylguanidine is preferably radioactive m-iodobenzylguanidine. Theradioisotope of iodine is preferably ¹²³I radioisotope, ¹²⁴Iradioisotope, ¹²⁵I radioisotope or ¹³¹I radioisotope, and morepreferably ¹²³I radioisotope or ¹³¹I radioisotope. In an embodiment, thecomposition of the present disclosure further comprises one or moreadditive agents. Said additive agents comprise niacinamide and benzylalcohol, and may further comprise sodium acetate.

The term “m-iodobenzylguanidine” refers to a compound having formulaC₈H₁₀IN₃ and having molar mass of 275.09 g/mol. Salt, hydrate andsolvate of “radiohalogenated benzylguanidine” are also encompassed bythe present disclosure. Preferably, the salt of radiohalogenatedbenzylguanidine is a non-nucleophilic salt, such as nitrate, sulfate orhemi-sulfate. According to the present disclosure, the preferred salt isa hemi-sulfate salt. In another preferred embodiment, the salt ofradiohalogenated benzylguanidine is used in the composition. In anotherpreferred embodiment, the hydrate of radiohalogenated benzylguanidine isused in the composition.

In another aspect, the radiopharmaceutical compositions according to thepresent disclosure comprise radiohalogenated benzylguanidine or apharmaceutically acceptable salt, hydrate or solvate thereof,niacinamide and benzyl alcohol.

In another aspect, the radiopharmaceutical compositions according to thepresent disclosure comprise radiohalogenated benzylguanidine or apharmaceutically acceptable salt, hydrate or solvate thereof,niacinamide, benzyl alcohol, and sodium acetate.

In another aspect, the radiopharmaceutical compositions of the presentdisclosure are devoid of paraben. Parabens includes without limitationmethyl paraben, propyl paraben, butyl paraben, ethyl paraben and thelike.

In another aspect, the radioactivity concentration of theradiopharmaceutical compositions of the present disclosure ranges fromabout 5 mCi/ml to 1 Ci/ml, from about 10 mCi/ml to 500 mCi/ml, fromabout 10 to 100 mCi/ml, from about 10 to 50 mCi/ml, or about 30 mCi/ml.

In another aspect, the radiochemical purity of the compositionsaccording to the present disclosure is at least 99% upon itspreparation. In an embodiment, the radiochemical purity of 99% ispresent on day 0 or day 1 upon the preparation of the composition. Theterm “radiochemical purity” as used herein, designates the percentage ofradioisotopes that are attached or bound within benzylguanidine per thetotal of radioactivity in the composition. Radiochemical impurity hereinis represented by the radioisotopes that are free (or unbound) in thecomposition. Day 0 indicates immediately after preparation of thecomposition; and day 1 means 24 hours after preparation of the same.

In yet another aspect, the radiochemical purity of the compositionsaccording to the present disclosure is at least 97% for at least twodays after the preparation of the composition. In yet another aspect,the radiochemical purity of the composition according to the presentdisclosure is at least 97% for at least four days after the preparationof the composition. In an embodiment of the invention, the compositionis stored at 5±3° C. (or 2-8° C.). In another embodiment of theinvention, the composition is stored at a temperature between 2° C. and30° C. In a further aspect, the radiochemical purity of the compositionaccording to the present disclosure is at least 95% for at least twodays after the preparation of the composition. In another furtheraspect, the radiochemical purity of the composition according to thepresent disclosure is at least 95% for at least four days after thepreparation of the composition. In an aspect of the present disclosure,the radiochemical purity of the composition is at least 99%, 98%, 97%,96%, 95% or 94% for at least 0, 1, 2, 3, 4 or 5 days from the day of itspreparation when stored on dry ice (−78±3° C.), freezer (−18±3° C.),refrigerator (at 5±3° C.), at room temperature (25±3° C.) or at anytemperature in between −78±3° C. and 25±3° C. In a preferred embodiment,the composition is frozen on dry ice after its preparation. Thecomposition is preferably shipped frozen on dry ice; the dry icesublimes during the transportation. Therefore, once received atdestination, the composition is at temperature that can vary from dryice temperature to room temperature. Upon receipt, the composition ispreferably removed from its shipping container and placed into arefrigerator at 5±3° C. Stability of composition is maintained up to itsexpiry date. In another embodiment of the invention, the composition isnot frozen after its preparation and shipped at a refrigeratedtemperature of about refrigerator (at 5±3° C.). In an embodiment, thecomposition of the present disclosure expires at 23:59, two days afterthe date of its manufacture. In another embodiment, the composition ofthe present disclosure expires at 23:59, four days after the date of itsmanufacture.

In an embodiment, the resulting radiochemical purity of a compositionimmediately after its preparation is at least 99%, 98% or 97%. Inanother embodiment, the resulting radiochemical purity of thecomposition two days after its preparation is at least 98%, 97%, 96% or95% when stored at a temperature from −78±3° C. to 25±3° C.

Radiochemical purity of a composition of radioactive halogenatedbenzylguanidine is the amount of radioactive halogen that is boundwithin the benzylguanidine compared to the total of radioactive halogenthat is present in the composition. Radiochemical purity is measured bya variety of analytical techniques such as high performance liquidchromatography (HPLC), paper chromatography, thin-layer chromatographyand electrophoresis. After separation, the distribution of radioactivityon the chromatogram is determined using an appropriate radiationdetector. The radiochemical purity of a composition is the percentage ofthe stated radionuclide that is present in the stated molecule. Thecomposition should maintain an acceptable radiochemical purity limitduring the whole shelf-life. Radiochemical impurities may arise duringthe preparation of the material or during storage, chemicaldecomposition or, because of radiation decomposition (radiolysis).

The compositions of the present disclosure may further comprise one ormore excipient or additives. The term “excipient or additive” means acomponent that has no diagnostic or therapeutic function. Examples ofexcipients are, without limitation, buffering components, acids, bases,osmolality adjusting agents, tonicity modifying agents, fillers,stabilizers, radioprotectants and lyoprotectants. The excipients thatare useful in preparing a pharmaceutical composition are generally safe,non-toxic and are acceptable for human pharmaceutical use. Combinationof excipients performing the same function may also be used to achievedesired composition characteristics.

When the radiopharmaceutical composition of the present disclosure isintended for parenteral administration, it may include one or morepharmaceutically acceptable carriers and excipients, including, but notlimited to, aqueous vehicles, water-miscible vehicles, non-aqueousvehicles, stabilizers, solubility enhancers, isotonic agents likemannitol, glucose, trehalose, dextran, buffering agents, antioxidants,suspending and dispersing agents, wetting or emulsifying agents,complexing agents, sequestering or chelating agents, cryoprotectants,lyoprotectants, thickening agents, pH adjusting agents and inert gases,radioprotectants like benzyl alcohol, niacinamide, ascorbic acid,gentisic acid, sodium sulfite, sodium metabisulfite, para amino benzoicacid (PABA), pyridoxine, and pyridoxal. When the pharmaceuticalcomposition of the present disclosure is intended for oraladministration, it may be in a liquid form or a solid form.

In one embodiment, the compositions of the present disclosure compriseradioactivehalogenated benzylguanidine or a pharmaceutically acceptablesalt, hydrate or solvate thereof, in combination with a tonicityadjuster, a buffer and a compound selected from the group consisting ofa stabilizer, a preservative, or a radioprotectant.

According to the present disclosure, the “radioprotectant” is aningredient which prevents the radiolysis of the composition and helps instabilizing the radiopharmaceutical compositions. Radioprotectant can beselected from the consisting of antioxidants, buffering agents,stabilizers, preservatives or combinations thereof.

According to the invention, the “stabilizer” can be selected from thegroup consisting of aminoethyl sulfonic acid, niacinamide, L-arginine,butylhydroxyanisol, L-cysteine, cysteine hydrochloride, diethanolamine,diethylene triamine pentaacetic acid, human serum albumin, hydrolyzedgelatin, inositol, D,L-methionine, polyoxyethylene castor, potassiumpyrosulfite, potassium thiocyanate, sodium gluconate, sodiumthioglycolate, trienthanolamine, zinc chloride solution, ascorbic acid,gentisic acid, nicotinic acid, para amino benzoic acid (PABA), ethylgallate, propyl gallate, riboflavin-5-phosphate, benzyl alcohol, and acombination thereof.

According to the present disclosure, the “preservative” can be selectedfrom the group consisting of benzalkonium chloride, benzethoniumchloride, benzyl alcohol, chlorobutanol, m-cresol, phenol,2-penoxyethanol, phenyl mercuric nitrate, thimerosal or combinationsthereof.

According to the present disclosure, the “buffer” or “buffering agent”can be selected from group consisting of sodium citrate, acid citrate,disodium citrate, trisodium citrate, sodium acetate, glacial aceticacid, sodium phosphate, monobasic potassium phosphate, dibasic potassiumphosphate, monobasic sodium phosphate, dibasic sodium phosphate,tribasic sodium phosphate, tris base, tris acetate, Tris HCl, meglumine,tartarate sodium/acid, sodium carbonate, sodium dihydrogen phosphate,and combinations thereof.

The “inert gas” according to the present disclosure can be selected fromgroup consisting of helium, neon, argon, nitrogen or combinationsthereof. In an embodiment of the invention, an inert gas is used toreplace the presence of air in a vial containing the composition of thepresent disclosure during transportation and storage, and until the vialis opened.

In one embodiment, the composition according to current invention isdevoid of paraben. Paraben includes without limitation any alkyl parabensuch as methyl paraben, propyl paraben, butyl paraben, ethyl paraben andthe like.

In one embodiment, the radioactivity of the radiopharmaceuticalcomposition ranges from about 1 mCi to about 1 Ci per container, about25 mCi to about 700 mCi per container, or about 30 mCi to about 450 mCiper container. In one embodiment, the volume of the radiopharmaceuticalcomposition ranges from about 0.4 ml to about 50 ml per container, fromabout 0.4 ml to about 10 ml per container, from about 0.4 ml to about 2ml per container, or of about 1 ml per container. In one embodiment, theconcentration of radiohalogenated benzylguanidine in theradiopharmaceutical composition is from about 0.10 mg/ml to about 10mg/ml, from about 0.50 mg/ml to about 2 mg/ml, or of about 0.83 mg/ml.

In a preferred embodiment, the preparation of radiohalogenatedbenzylguanidine (labelling reaction) is obtained by the replacement ofits non-radio-active iodine atom with a radioactive isotope of halogensuch as a radioisotope of iodine, a radioactive isotope of fluor, aradioactive isotope of brome or a radioactive isotope of astitine. In anembodiment, the process consists of adding to a vial containing a givenamount of cold MIBG (i.e. non-radioactive MIBG), the appropriate volumeof copper catalyst solution, buffer solution and radioactive halogenisotope solution. After adding a few anti-bumping granules, the vial issealed and heated for 40-50 minutes. Upon that time the labellingreaction is completed and the reaction mixture is transferred with hotwater into a purification column containing anion exchange resin. Mostor all the content in copper catalyst is removed by the anion exchangeresin. The purified labelled benzylguanidine is collected in a vialcontaining a diluent solution. Depending of the reaction yield andrecovery and the customer requested dose, the labelled benzyl guanidinecan be further diluted with the diluent solution and dispensed. In anembodiment, the radiopharmaceutical composition may contain trace ofcopper catalyst, and preferably no more than 0.1 mg/ml, preferably nomore than 0.03 mg/ml, or preferably no more than 0.02 mg/ml.

In one embodiment of the present disclosure, the composition can bedirectly administered to the patient or can be further diluted with asuitable biocompatible diluent prior administration.

The term “about” as used herein preferably refers to ±10% of the valuesmentioned herein.

In one embodiment, the composition according to the present disclosurehas a shelf-life of at least 5, 4, 3, or 2 days, and more preferably atleast 2 days, and more preferably of at least 4 days.

In another embodiment of the present disclosure, a combination ofniacinamide and benzyl alcohol is used to preserve radiochemical purityof the composition with high activity during shelf life of the product.Preferably, niacinamide and benzyl alcohol are present in an optimumratio that provides an improved radiochemical purity during shelf-lifeof the composition. It has been found that benzyl alcohol andniacinamide provide a synergistic effect in stabilizing theradiopharmaceutical composition of present disclosure. Furthermore, thecomposition pH is preferably maintained in an optimum range i.e. fromabout 3 to 8, from about 3 to 7, from about 4 to 7.5, from about 4 to 6,from about 6 to 7.5, from about 6 to 7, from about 5 to 6, from about4.5 to 5, or 5.0±0.1, or 4.5±0.1.

Niacinamide concentration in the composition of the present disclosure,is preferably about 0.5 to 70.0 g/100 ml, preferably about 0.5 to 10.0g/100 ml, preferably about 1.0 to 5.0 g/100 ml, preferably about 1.0 to2.0 g/100 ml, preferably about 1.5 to 2.0 g/100 ml, and preferably about1.6 g/100 ml.

Benzyl alcohol concentration in the composition of the presentdisclosure, is preferably 2.0% (v/v) or lower, preferably from 0.01%(v/v) to 2.0% (v/v), preferably from 0.05% (v/v) to 2.0% (v/v),preferably from 0.9% (v/v) to 2.0% (v/v), preferably from 0.05% (v/v) to1.6% (v/v), preferably from 0.05% to 1.8%, preferably from 0.05% to1.6%, preferably from 0.05% to 1.2%, preferably about 0.01%, preferablyabout 0.05%, preferably about 0.5%, preferably about 0.9%, preferablyabout 1.0%, or preferably about 1.6%. The concentration of benzylalcohol should not exceed toxicity level for intravenous administrationas set forth by Health Canada, FDA, EMA, and other regulatory agencies.

In another embodiment, the composition according to the presentdisclosure has a radiochemical purity of at least 90% and preferably atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

In another embodiment of present disclosure, the radiopharmaceuticalcomposition comprises radiohalogenated benzylguanidine or apharmaceutically acceptable salt, hydrate or solvate thereof, and one ormore stabilizers that is/are not selected from the group consisting ofparabens. Said one or more stabilizers is preferably a combinationbenzyl alcohol and niacinamide. Optionally, the composition of thepresent disclosure also comprises a buffer. Preferably, said buffercomprises a combination of sodium acetate trihydrate and sodiumchloride. Any pharmaceutically acceptable buffers are contemplated toprepare the composition of the present disclosure as long as the desiredpH is reached and maintained. Preferably, the concentration of sodiumacetate trihydrate varies between 0.01 and 20 mg/ml, between 0.05 and 10mg/ml, between 0.05 and 5 mg/ml, between 0.1 and 2 mg/ml, between 0.5and 2 mg/ml, or from 1.0 to 1.3 mg/ml.

In another aspect, the radiopharmaceutical composition of the presentdisclosure, comprises radiohalogenated benzylguanidine, benzyl alcoholand niacinamide, wherein the ratio of benzyl alcohol:niacinamide rangesfrom about 1:1 to about 1:35, preferably from about 1:1 to about 1:15,preferably from about 1:1 to about 1:10, preferably from about 1:1 toabout 1:5, preferably from about 1:1 to about 1:2. In yet another aspectof the present disclosure, the ratio of niacinamide:benzyl alcoholranges from about 1:1 to about 1:5, preferably from about 1:1 to about1:3, and preferably from about 1:1 to about 1:2. Preferably, the ratioof benzyl alcohol:niacinamide is from about 1:0.5 to 1:35, preferablyfrom about 1:0.8 to 1:32, preferably from about 1:0.8 to 1:10,preferably from about 1:0.8 to 1:2, preferably from about 1:0.8 to 1:2,preferably about 1:1, preferably about 1:0.9, or preferably about 1:0.8.In another embodiment, the composition comprises a ratio ofniacinamide:benzyl alcohol that is from about 1:1 to 1:5, preferably 1:1to 1:3.

In another aspect, the radiopharmaceutical composition of the presentdisclosure is suitable for oral or parental administration. Parentaladministration includes intravenous administration. In one embodiment ofthe present disclosure, the pharmaceutical composition provided hereinmay be formulated in any dosage form that is suitable for parenteraladministration, including solution, lyophilized powder, suspension,emulsion, micelle, liposome, microsphere, nanosystem, and solid formsuitable for dissolution or suspension in a liquid prior toadministration. In one embodiment of the present disclosure, thepharmaceutical composition provided herein may be formulated in anydosage form that is suitable for oral administration.

In one embodiment, the present disclosure also provides a method ofpreparing a pharmaceutical composition of radiohalogenatedbenzylguanidine, or a pharmaceutically acceptable salt, hydrate orsolvate thereof.

The method preferably comprises the steps of:

-   -   (i) mixing benzyl alcohol with water;    -   (ii) adding niacinamide and optionally sodium acetate and/or        sodium chloride to the solution prepared at step (i);    -   (iii) mixing the solution of step (ii);    -   (iv) optionally adjusting the pH between 3.0-7.0;    -   (v) optionally adding water to the solution prepared at        step (iv) for adjusting the total volume of the solution; and    -   (vi) mixing radiohalogenated benzylguanidine with the solution        of step (v); and    -   (vii) optionally filter the solution of step (vi).

In another aspect of the present disclosure, provided herein is a methodfor preparing a radiopharmaceutical composition of radiohalogenatedbenzylguanidine comprising:

-   -   (i) preparing a solution of benzyl alcohol and water;    -   (ii) adding niacinamide, sodium acetate and sodium chloride to        the solution of step (i);    -   (iii) mixing the solution of step (ii)    -   (iv) optionally adjusting the pH to about 5.0;    -   (iv) completing the solution of step (iv) with water until the        desired volume is reached;    -   (v) adding radiohalogenated benzylguanidine to the solution of        step (iv); and    -   (vi) optionally filtering the solution of step (v).

Water used herein is preferably water for injection. Adjusting the pH isperformed with addition of an acid or a base, wherein said acid ispreferably HCl or sodium chloride, and said base is preferably NaOH orsodium acetate. The filtration step (vii) is optional and can beperformed as a sterilization step. Preferably, a 0.22 μm pore sizefilter is used. In an embodiment of the invention, the method is exemptof addition of paraben at any step thereof.

In an embodiment, the resulting radiochemical purity of the compositionwithin 24 hours of its preparation (i.e. at day 0) is at least 99%, 98%or 97%. In another embodiment, the resulting radiochemical purity of thecomposition two days after its preparation is at least 98%, 97%, 96% or95% when stored between −78±3° C. and 25±3° C.

The pharmaceutical composition provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationcan be packaged in an ampoule, a vial, a syringe, or a prefilledsyringe. The single dosage formulation can be packaged into one or morecapsules. The final composition of present disclosure is preferablypacked in a 30 mL Type I glass vial capped with Teflon-coated, butylrubber stopper and aluminium seal. In one embodiment of the presentdisclosure, the composition can be filled into a container such as avial, an ampoule, or a prefilled syringe of 0.5 ml, 1 ml, 2 ml, 5 ml, 10ml, 20 ml, 25 ml, 30 ml, 60 ml or 100 ml.

In yet another aspect, the radiopharmaceutical composition of thepresent disclosure are suitable for use in the detection andlocalization of primary or metastatic pheochromocytoma, neuroblastoma,paraganglioma, neuroendocrine tumors of gastroenteropancreatic tract,medullary thyroid carcinoma, and diseases resulting from myocardialischemia and cardiomyopathy. The composition of the present disclosureis useful for scintigraphic assessment of sympathetic innervation of themyocardium. The composition of the present disclosure is also useful forthe treatment of patients with malignant or recurrent pheochromocytoma,neuroblastoma, paraganglioma (PPGL), or neuroendocrine tumors of thegastroenteropancreatic tract.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther defined by reference to the following examples describing indetails radiopharmaceutical compositions of the present disclosure. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe scope of the invention. Following examples are set out to illustratethe invention and do not limit the scope of the invention.

EXAMPLES

The following examples are intended to further illustrate certainpreferred embodiments of the invention and are not limiting in nature.

Example 1: MIBG Labelling Reaction

Radioactive MIBG is prepared by replacement of the non-radioactiveiodine atom of cold MIBG with ¹³¹I. More particularly, in a vialcontaining 20 mg of cold MIBG, were added 1.3 Ci of Na¹³¹I solution,copper catalyst solution, and sodium acetate pH 4.5 buffer solution.After adding a few anti-bumping granules, the vial is sealed and heatedfor 40-50 minutes. Then, the reaction mixture is transferred with hotwater (eluant) into the purification column containing anion exchangeresin. The purified labelled MIBG is collected into a vial containingthe diluent solution (2×). The purification column is used to eliminatecopper catalyst from the labelled MIBG solution.

Example 2: Preparation of the Diluent Solution

The diluent solution is prepared in a 2× concentration and in a 1×concentration. The diluent solution 2× is used to receive the labelledMIBG from the purification column and its eluant. For instance, if 8 mlof eluant (hot water) is used for eluting the labelled MIBG from thecolumn, then 8 ml are used in the collecting vial, and thus theresulting concentration is 1×.

Six (6) diluent solutions 1× have been prepared in order to test theimpact on various ratios of benzyl alcohol:niacinamide on theradiochemical purity of the radioiodinated MIBG composition of thepresent disclosure. The contents of these 6 diluent solutions 1× are asfollow in Table 1.

TABLE 1 Diluent solutions 1X with various ratios of benzylalcohol:niacinamide Benzyl Alcohol Niacinamide No. (% v/v) (g/100 ml) pHRatio 1 0 0 5.0 0:0 2 0 1.6 5.0 0:1 3 0.05 1.6 5.0  1:32 4 0.9 1.6 5.0 1:1.8 5 1.9 1.6 5.0   1:0.84 6 0.9 0 5.0 1:0

The diluent solution was prepared by:

i) Adding a volume of benzyl alcohol to water for injection, and mixing;

ii) Adding niacinamide to the solution of step (i), and mixing;

iii) Adjusting the pH of the solution of step (ii) to 5.0; and

iv) Adding water for injection so as to reach the desired final volume.

Example 3: Preparation of the Labelled MIBG Composition

A resulting labelled MIBG composition is obtained by collecting thepurified labelled MIBG from the purification column in the diluentsolution 2×, and mixing. The volume of elution (containing the labelledMIBG) is identical to the volume of diluent solution 2× in thecollecting vial, in order to obtain a resulting concentration of thestabilizers and excipients of 1×.

When preparing doses of radioiodinated MIBG for administration anddilution is needed, the solution in the collecting vial is diluted withthe diluent solution 1×.

Example 4: RadioChemical Purity (RCP) Assays with HPLC

Radiochemical purity (RCP) can be tested with several methods asdescribed in the specification. In the present example, HLPC method wasused as follow: Inject up to 20 uL of the labelled MIBG solution(sample) into the chromatographic system at a flow rate of 1 mL/min.Record the chromatogram. Two main peaks should be observed: one with aretention time of about 8 min for labelled MIBG and one at about 2 minfor free iodine. Express the areas under the peaks as percentage of thetotal radioactivity measured. The percentage value for the labelled MIBGpeak corresponds to the radiochemical purity (RCP) of the preparation.

Characteristics of the chromatographic system that have been used inthis example are the following Table 2.

TABLE 2 Chromatographic system characteristics HPLC Column: Luna 10 μ,C18, 250 × 4.6 mm Mobile Phase Water (600 ml):acetonititrile (200ml):TFA (4 ml) Mode: Isocratic Acquisition Time: 10 min Flow rate: 1mL/min UV Wavelength: 229 nm Radioactive detector NaI Injection Volume:10-100 μL

Example 5: Variation of Benzyl Alcohol:Niacinamide Ratio Assays

Experiments were performed to determine the role of benzyl alcohol andniacinamide in the preservation of the radiochemical purity of ¹³¹IMIBG. In this experiment, six (6) samples were prepared each containing50 mCi ¹³¹I MIBG in a composition of 2.5 mL total volume, and using thediluent solutions as described in Table I. Each ¹³¹I MIBG compositionwas stored for a period of four (4) days at 5±3° C. and theradiochemical purity (RCP) was monitored daily. Radiochemical purity wasmeasured using HPLC method. The results of the radiochemical puritymonitoring are reported in Table 3.

TABLE 3 Daily RCP results with varying ratios of benzylalcohol:niacinamide ¹³¹I MIBG Composition Benzyl with DiluentAlcohol:Niacinamide RCP (%) Solution No. Ratio Day 0 Day 1 Day 2 Day 3Day 4 1 0:0 99 65 42 24 27 2 0:1 97 96 95 92 3  1:32 99 98 98 97 4 1:1.8 98 99 98 97 5   1:0.84 97 98 98 97 6 1:0 92 80 69 68

Results from Table 3 clearly shows that the absence of niacinamide andbenzyl alcohol (No. 1) is detrimental to the preservation of theradiochemical purity of ¹³¹I in MIBG; since after 4 days, said puritydrastically went down from 99% to 27%. Results from Table 3 also clearlyshows that neither niacinamide nor benzyl alcohol alone (Nos. 2 and 6)is sufficient to preserve the radiochemical purity of the composition,since the radiochemical purity has decreased to 92% and 68%respectively, after 4 four days. However, a significant preservation ofthe radiochemical purity of the ¹³¹I MIBG composition is obtained whenbenzyl alcohol and niacinamide are combined together (Nos. 3, 4 and 5).Although diluent solution Nos. 3, 4 and 5 have provided similar RCP, thediluent solutions No. 3 and No. 4 are advantageous in that they use alow concentration of benzyl alcohol. The resulting RCP results haveshown that it is possible to maintain a radiochemical purity as high as97% after 4 days when stored in the refrigerator, without using harmfulexcipients such as parabens.

While this invention has been described in detail with reference tocertain preferred embodiments, it should be appreciated that the presentdisclosure is not limited to those precise embodiments. Rather, in viewof the present disclosure, which describes the current best mode forpracticing the invention, many modifications and variations wouldpresent themselves to those skilled in the art without departing fromthe scope, and spirit of this invention.

What is claimed:
 1. A radiopharmaceutical composition comprising:radiohalogenated benzylguanidine selected from ¹³¹I-benzylguanidine or apharmaceutically acceptable salt, hydrate or solvate thereof; and,radioprotectants comprising benzyl alcohol and niacinamide, wherein thebenzyl alcohol and niacinamide are present in a ratio of about 1:0.8 to1:32, wherein the radioactivity concentration of the composition isabout 20 mCi/mL to about 1 Ci/mL, wherein the composition has aradiochemical purity of at least 99% at the time immediately followingits preparation from its constituent ingredients, and wherein thecomposition is free of paraben.
 2. The radiopharmaceutical compositionof claim 1, wherein the radiohalogenated benzylguanidine is¹³¹I-benzylguanidine.
 3. The radiopharmaceutical composition of claim 1,wherein the radiohalogenated benzylguanidine is present in aconcentration from 0.10 mg/ml to 10 mg/ml.
 4. The radiopharmaceuticalcomposition of claim 1, wherein the benzyl alcohol is present in aconcentration from 0.9% (v/v) to 2.0% (v/v).
 5. The radiopharmaceuticalcomposition of claim 1, wherein the niacinamide is present in aconcentration from 0.5 g to 10 g/100 ml.
 6. The radiopharmaceuticalcomposition of claim 1, wherein the benzyl alcohol and niacinamide arepresent in the composition in a ratio of from 1:1 to 1:5.
 7. Theradiopharmaceutical composition of claim 6, wherein the benzyl alcoholand niacinamide are present in the composition in a ratio of from 1:1 to1:3.
 8. The radiopharmaceutical composition of claim 7, wherein thebenzyl alcohol and niacinamide are present in the composition in a ratioof about 1:1.
 9. The radiopharmaceutical composition of claim 1, whereinthe benzyl alcohol and niacinamide are present in the composition in aratio of about 1:1.8.
 10. The radiopharmaceutical composition of claim1, wherein the composition has a radiochemical purity of at least 97%following four days of storage at 5±3° C. after its preparation from itsconstituent ingredients.
 11. The radiopharmaceutical composition ofclaim 1, wherein the composition has a radiochemical purity of at least95% at two days following its preparation when stored at any temperaturefrom 78±3° C. to 25±3° C.
 12. The radiopharmaceutical composition ofclaim 1, wherein the composition has a radiochemical purity of at least95% at two days following its preparation when stored at a temperatureof 5±3° C.
 13. The radiopharmaceutical composition of claim 1, whereinthe composition has a pH from 3.0 to 7.0.
 14. The radiopharmaceuticalcomposition of claim 13, wherein the pH is 5.0±0.1.
 15. Theradiopharmaceutical composition of claim 1, wherein the radioprotectantsconsist of benzyl alcohol and niacinamide.
 16. The radiopharmaceuticalcomposition of claim 1, wherein the radioprotectants do not includegentisic acid.
 17. The radiopharmaceutical composition of claim 1,wherein the composition further comprises a buffer comprising sodiumacetate and sodium chloride.
 18. The radiopharmaceutical composition ofclaim 1, wherein the composition is prepared by a method comprising thesteps of: (i) combining benzyl alcohol with water to form a combination;(ii) adding niacinamide to the combination of step (i), and mixing;(iii) adjusting the pH of the combination from 3.0 to 7.0; and (iv)adding ¹³¹I-benzylguanidine to the pH-adjusted combination of step(iii).
 19. The radiopharmaceutical composition of claim 18, wherein thestep (ii) of the method further comprises the addition of sodium acetateand sodium chloride.
 20. The radiopharmaceutical composition of claim 1,wherein the composition is a lyophilized powder, solution, suspension oremulsion.
 21. The radiopharmaceutical composition of claim 1, whereinthe composition is provided in a container selected from the groupconsisting of a vial, an ampoule, a prefilled syringe, and a capsule.22. A radiopharmaceutical composition comprising: radiohalogenatedbenzylguanidine selected from ¹³¹I-benzylguanidine or a pharmaceuticallyacceptable salt, hydrate or solvate thereof; and, radioprotectantscomprising benzyl alcohol and niacinamide, wherein the benzyl alcoholand niacinamide are present in a ratio of about 1:0.8 to 1:32, whereinthe radioactivity concentration of the composition is about 20 mCi/mL toabout 1 Ci/mL, wherein the composition has a radiochemical purity of atleast 99% at the time immediately following its preparation from itsconstituent ingredients, and wherein the composition has a pH from 3.0to 7.0.
 23. The radiopharmaceutical composition of claim 22, wherein thebenzyl alcohol is present in a concentration from 0.9% (v/v) to 2.0%(v/v).
 24. The radiopharmaceutical composition of claim 22, wherein theniacinamide is present in a concentration from 0.5 g to 10 g/100 ml. 25.The radiopharmaceutical composition of claim 22, wherein the compositionhas a radiochemical purity of at least 97% following four days ofstorage at 5±3° C. after its preparation from its constituentingredients.
 26. A radiopharmaceutical composition comprising:radiohalogenated benzylguanidine selected from ¹³¹I-benzylguanidine or apharmaceutically acceptable salt, hydrate or solvate thereof; and,radioprotectants comprising benzyl alcohol and niacinamide, wherein thebenzyl alcohol and niacinamide are present in a ratio of about 1:0.8 to1:32, and, benzyl alcohol is present in a concentration from 0.9% (v/v)to 2.0% (v/v), wherein the radioactivity concentration of thecomposition is about 20 mCi/mL to about 1 Ci/mL, and wherein thecomposition has a radiochemical purity of at least 99% at the timeimmediately following its preparation from its constituent ingredients.27. The radiopharmaceutical composition of claim 26, wherein theniacinamide is present in a concentration from 0.5 g to 10 g/100 ml. 28.The radiopharmaceutical composition of claim 26, wherein the compositionhas a radiochemical purity of at least 97% following four days ofstorage at 5±3° C. after its preparation from its constituentingredients.
 29. A method for the detection or localization in a subjectof primary or metastatic pheochromocytoma, neuroblastoma, paraganglioma,neuroendocrine tumor of gastroenteropancreatic tract, medullary thyroidcarcinoma, or a disease resulting from myocardial ischemia andcardiomyopathy, the method comprising administering to the subject theradiopharmaceutical composition of claim 1, and, performingscintigraphic imaging in order to detect or localize the primary ormetastatic pheochromocytoma, neuroblastoma, paraganglioma,neuroendocrine tumor of gastroenteropancreatic tract, medullary thyroidcarcinoma, or a disease resulting from myocardial ischemia andcardiomyopathy in the subject.
 30. A method for diagnosing or treatingin a subject pheochromocytoma, neuroblastoma, paraganglioma, orneuroendocrine tumor of the gastroenteropancreatic tract, the methodcomprising administering to the subject the radiopharmaceuticalcomposition of claim 1.